AZD is a disease in which amyloid β accumulates mainly around nerve cells and it causes nerve injuries and cerebral hypofunction mainly involving cerebral atrophy and dementia. Diffuse cerebral atrophy including that of the hippocampus and the cerebral cortex such as the frontal and parietal lobes is observed by imaging of the head in AZD. Agents that have been found to have efficacy in ameliorating dementia are already present. However, such agents cannot stop the progression of the condition. None of these agents have been successful in the long-term prevention or amelioration of cognitive decline and complete cure of the disease. Many clinical trials using anti-inflammatory steroids or non-steroidal anti-inflammatory drugs (hereinafter, referred to as NSAIDs) have been carried out based on the finding that inflammation in the brain is involved in the progression of AZD pathologies. Taking into consideration both the efficacy and side effect of respective drugs, however, the overall report that “the use of these drugs cannot be recommended for the treatment of Alzheimer's disease” has been made (Non Patent Document 1).
CAA is a disease in which amyloid β accumulates mainly in the cerebrovascular vessel and it causes brain injuries such as local circulatory dysfunction in the brain (white matter lesions), intracranial bleeding and multiple cerebral micro-bleeding (single, multiple, or bilateral), and epilepsy seizure. Characteristic accumulation of amyloid β on the cerebrovascular wall is observed in histopathological examinations for CAA. Besides, CAA is known to be associated with infiltration of various inflammatory cells such as small lymphocytes, macrophages, acidophiles, and multinucleated giant cells and a large number of micro-bleeding. Unfortunately, their causes are not known and, like AZD, no radical preventive or therapeutic agent (effective in suppressing the progression of pathologies, but not for symptomatic therapies) for CAA has been developed yet.
The progress in head MRI image has made T2-weighted imaging (T2-W1) in practical use and identification of asymptomatic or symptomatic cerebral micro-bleeding that could not be found has thereby become possible. CAA has become possible to be diagnosed by detection of deep white matter lesions and multiple micro-bleeding observed in MRI images, without conventional biopsies and pathological diagnoses of the brain tissue. However, no radical preventive or therapeutic agents for the disease has been developed and only surgical treatments for some intracranial bleeding and symptomatic therapies for epilepsy seizures have been practiced.
For CAA, efficacy of therapies using anti-inflammatory agents such as high dose steroid (glucocorticoid) therapies has been suggested as well as for AZD (Non Patent Document 2). However, administration of high doses of steroid is known to be associated with severe side effects such as susceptibility to infection due to the suppression of immunocompetence and accompanying infections with viruses, bacteria, and fungi; gastric ulcer formation and gastrointestinal bleeding; decreased bone density and increased proneness to bone fracture; impaired glucose tolerance and sudden hyperglycemia and dehydration; appearance of various psychiatric symptoms including depression; and adrenal insufficiency. Steroids have a wide suppressing effect on protective responses of the body to infections. In the case that a CAA-like vasculitis is associated with some infection, a long-term administration of a steroid might aggravate the condition. Since a slight side effect may become fatal in both the diseases AZD and CAA and these diseases may develop in elderly patients, some patients stop treatment halfway or reduce the dose of steroid, being subjected to the risk of exacerbation (rebound) of symptoms.
CAA, as well as AZD, is considered to involve the mechanism of autoimmunity. Efficacy of combination therapies of an immunosuppressive agent (such as cyclophosphamide) and a high dose of steroid, based on the idea, has been reported (Non Patent Document 2). However, this method has not become a common practice. It is not known whether the autoimmunity attacks normal cerebrovascular vessels or a damaged intravascular material to be removed or amyloid β, which acts as a tissue damaging factor.
Iguratimod (or T-614), chemical name: N-(3-formamido-4-oxo-6-phenoxy-4H-chromen-7-yl) methanesulfonamide (Formula (A)) is an agent classified in an immunomodulator and different from conventional antirheumatic drugs (Patent Document 1). Human use (a clinical trial) was started in about 2003. Iguratimod is characterized by suppressing effects, in particular, on the production of interleukin-1 and 6 (IL-1/6) and tumor necrosis factor (TNFα) from monocyte lineage cells (macrophages) in inflammation. No conventional NSAIDs (for example, indometacin) and disease modifying antirheumatic drugs (for example, salazosulfapyridine, SASP) have been found to have such effects. Such effects are considered to be unique effects of iguratimod, which has the “chromone structure” (Formula (B)) (Non Patent Document 3).

As therapeutic drugs for rheumatoid arthritis, efficacy of methotrexate (hereinafter, referred to as MTX), SASP, leflunomide, or cyclophosphamide, which are classified in immunosuppressive agents, has been already reported. And iguratimod has been also found to exhibit efficacy equivalent to MTX and SASP (Non Patent Document 4). Other therapeutic agents for rheumatoid arthritis include rituximab (trade name “Rituxan”) effective against malignant lymphoma, the antibiotics minocycline and tetracycline, the hyperlipemic therapeutic drug statin, the multiple myeloma therapeutic drug thalidomide, and anti-JAK inhibitors, which inhibit JAK in signal transduction systems, suggesting the special nature of the disease rheumatoid arthritis.
Interleukin (IL) is the name of substances that are secreted from leukocytes and involved in the inflammatory reaction. Interleukins are numbered in the order of their identification. Over 30 ILs are now known. IL-1 and IL-6 are characteristic in that they are produced by locally activated monocytes (macrophages) and distinguished from cytokines that are produced by other cells classified as inflammatory cells such as T cells, B cells, NK cells, neutrophiles, mast cells, and peripheral blood monocytes.